PROCESS FOR PREPARING 6-ARYL-4H-S-TRIAZOLO[3,4-c]-THIENO[2,3-e]-1,4-DIAZEPINES

ABSTRACT

An improved process for preparing 6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula I,  
                 
wherein: 
     R 1  is a hydrogen or halogen atom or a C 1 -C 6  alkyl group,    R 2  is a hydrogen or halogen atom or a C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 3 -C 6  cycloalkyl group or a 5- or 6-membered oxygen-, sulphur- or nitrogen-containing heterocyclic group which may optionally be substituted at the nitrogen atom by a C 1 -C 3  alkyl group, and    R 3  is a hydrogen or halogen atom.

RELATED APPLICATIONS

This is a continuation application of divisional application Ser. No.11/074,198, filed on Mar. 7, 2005, the entirety of which is incorporatedherein by reference, which claims benefit of U.S. patent applicationSer. No. 10/096,809, filed on Mar. 12, 2002, now U.S. Pat. No.6,884,886, the entirety of which is incorporated herein by reference,and U.S. Provisional Application Ser. No. 60/289,880, filed on May 9,2001, the entirety of which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to a process for preparing6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula I,

wherein R¹, R² and R³ have the meanings given, from a5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formula II

BACKGROUND TO THE INVENTION

6-Aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines, particularlybrotizolam (R¹=Br, R²=methyl, R³=Cl), are known for example from U.S.Pat. No. 4,094,984 and are valuable medicaments which have sedativeproperties, in particular, and may be used for treating sleep disorders.

However, the preparation described therein, starting from a5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formula TI, isunsuitable for production on an industrial scale, as the intermediateproducts involved, such as for example5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-thiones, have to beisolated, and when reacted give off foul-smelling and in some casestoxic thiols which may lead to contamination of the products.

The aim of the present invention is therefore to provide a process whichmakes it possible to synthesise, work up, purify and isolate6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula I onan industrial scale while overcoming the disadvantages mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula I,wherein

R¹ denotes a hydrogen or halogen atom or a C₁-C₆ alkyl group,

R² denotes a hydrogen or halogen atom or a C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, C₃-C₆ cycloalkyl group or a 5- or 6-membered oxygen-,sulphur- or nitrogen-containing heterocyclic group which may optionallybe substituted at the nitrogen atom by a C₁-C₃ alkyl group, and

R³ denotes a hydrogen or halogen atom, can be produced on an industrialscale if a 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formulaII,

wherein R¹ and R³ are as herein defined,

-   -   (a) is treated with a chlorinating agent,    -   (b) the resulting 5-aryl-2-chlorothieno[2,3-e]-1,4-diazepine of        formula III,        -   wherein R¹ and R³ are as herein defined, is reacted with an            acylhydrazine of formula IV            R²—CO—NH—NH₂        -   wherein R² is as hereinbefore defined, and    -   (c) the product thus obtained is treated with a base.

The invention thus relates to a process for preparing the compounds offormula I from compounds of formula II according to steps (a), (b) and(c) mentioned above.

The invention also relates to a process for preparing a compound offormula I wherein R¹ denotes bromine, in which a compound of formula V,

wherein R³ is as hereinbefore defined,is subjected to the following reactions one after another:

-   (d) cyclisation under water-cleaving conditions;-   (e) reacting the product obtained in step d) with a brominating    agent;-   (f) converting the compound of formula II thus obtained wherein R¹    denotes bromine into the compound of formula I according to    steps (a) to (c),    characterised in that steps (d) and (e) are carried out in a one-pot    process.

The invention also relates to5-aryl-2-chlorothieno[2,3-e]-1,4-diazepines of formula III,

wherein R¹ and R³ have the meanings given, particularly7-bromo-5-(2-chlorophenyl)-2-chlorothieno[2,3-e]-1,4-diazepine.

The term “alkyl” as used hereinbefore and hereinafter with regard to thegroups R¹ and/or R² denotes a straight-chain or branched alkyl groupwith up to 6 C atoms, preferably 1 to 4 C atoms. Particularly preferredare methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl,particularly methyl.

The term “hydroxyalkyl” as used hereinbefore and hereinafter with regardto the group R² denotes a straight-chain or branched alkyl group with upto 6 C atoms, preferably 1 to 4 C atoms, which is substituted by ahydroxy group. ω-Hydroxyalkyl groups with 1 to 3 C atoms, particularlyhydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl are preferred.

The term “cycloalkyl” as used hereinbefore and hereinafter with regardto the group R² denotes a cyclic alkyl group with 3 to 6 C atoms,preferably 5 or 6 C atoms, particularly cyclopentyl and cyclohexyl.

The term “heterocyclic group” as used hereinbefore and hereinafter withregard to the group R² denotes a saturated or unsaturated 5- or6-membered heterocyclyl group, which contains in addition to carbonatoms and at least one heteroatom selected from among nitrogen, oxygenand sulphur. The following heterocyclyl groups are preferred:

saturated or aromatic 5- or 6-membered heterocyclyl groups which

-   -   contain one or two nitrogen atoms, particularly pyrrolidyl,        pyrazolyl, imidazolyl, pyridyl, pyrimidyl, piperidyl and        piperazyl, or    -   a nitrogen atom and an oxygen or sulphur atom, particularly        morpholino and thiomorpholino,    -   contain an oxygen atom, particularly tetrahydropyranyl and        tetrahydrofuranyl.

The term “one-pot process” as used hereinbefore and hereinafter for thesequence of certain reaction steps denotes the succession of two or moresynthesis steps occurring one after another, with the intermediateproduct obtained in a first or second synthesis step being used in thenext synthesis step without any isolation or purification. Preferably,the subsequent reaction step is carried out in the same reaction vesseland optionally in the presence of the reaction medium in which theprevious reaction step was carried out.

In a preferred embodiment the groups R¹ to R³ have the followingmeanings:

R¹ denotes halogen or methyl, particularly bromine,

R² denotes hydrogen or methyl, particularly methyl, and

R³ denotes halogen, particularly chlorine.

In a preferred embodiment of the process according to the invention forpreparing the compound of formula I:

-   -   in step (a) the compound of formula (II) is reacted with        phosphorus pentachloride in the presence of an inert diluent and        a tertiary amine;    -   in step (b) the compound of formula (III) is reacted at a        temperature below 100° C. with acetic acid hydrazide in the        presence of an inert diluent.    -   in step (c) the compound obtained in step (b) is treated with        aqueous sodium hydroxide solution at a temperature of 0° C. to        50° C.;    -   the reaction sequence of steps (a) to (c) is carried out in a        one-pot process.        Stage II→III        Step (a)

The reaction of the compound of formula II with the chlorinating agentis generally carried out in the presence of an inert diluent.

Preferably the compound of formula II is reacted with a chlorinatingagent selected from among thionyl chloride, sulphuryl chloride, titaniumtetrachloride, oxalyl chloride, phosgene, di- and triphosgene,phosphorus trichloride, phosphorus oxychloride, phosphorus pentachlorideand antimony pentachloride, conveniently in a diluent such astetrahydrofuran, dioxane, toluene, dichloromethane, chloroform orchlorobenzene, or mixtures of these diluents, optionally in the presenceof an organic base, e.g. triethylamine, N-ethyldiisopropylamine,pyridine or 4-dimethylaminopyridine, at temperatures from −20 to +60°C., preferably −10 to +20° C. The reaction is generally carried out atnormal pressure, using 0.9 to 2.0, preferably 1.1 to 1.9, particularly1.2 to 1.4 mol of a chlorinating agent based on 1 mol of the compound offormula II.

The reaction is generally complete, under the conditions specified,after 15 to 600 minutes, preferably 30 to 180 minutes. The crude productobtained is generally further processed in the next step without anyother purification.

In a particularly preferred embodiment of the process according to theinvention a suspension of the compound of formula II in pyridine anddichloromethane is added dropwise to a suspension of 1.1 to 1.5 mol ofphosphorus pentachloride based on 1 mol of the compound of formula II indichloromethane at 0 to 20° C. with cooling. The mixture is stirred for30 to 120 minutes at about 10

Stage III→I

Step (b)

The reaction of the compound of formula III with the compound of formulaIV generally takes place in an inert solvent.

Preferably, the compound of formula III is reacted with a compound offormula IV, particularly acetic acid hydrazide, conveniently in adiluent such as tetrahydrofuran, dioxane, toluene, dichloromethane,chloroform or chlorobenzene, or mixtures of these diluents, particularlyin a mixture of dichloromethane and tetrahydrofuran, optionally in thepresence of an organic base, e.g. triethylamine,N-ethyldiisopropylamine, pyridine or 4-dimethylaminopyridine, and theother reaction products formed in step (a), e.g. phosphorus oxychloride,at temperatures from 0 to 100° C., preferably 10 to +90° C. The reactionis generally carried out at normal pressure, using 0.9 to 3.0,preferably 1.5 to 2.5, particularly 1.8 to 2.2 mol of a compound offormula IV based on 1 mol of the compound of formula III. The reactionis generally complete, under the conditions specified, after 1 to 48hours, preferably 5 to 24 hours. The crude product obtained is generallyfurther processed in the next step without any other purification.

In a particularly preferred embodiment of the process according to theinvention, a heated solution of about 2 equivalents of acetic acidhydrazide in tetrahydrofuran based on 1 equivalent of formula III isadded dropwise with cooling at 0-30° C. to the reaction mixture obtainedin step (a). The resulting mixture is then stirred for a further 0.5 to2 hours at ambient temperature and then refluxed for 5-20 hours. Thebrotizolam is obtained as the hydrochloride/phosphate, and thebrotizolam is liberated by the subsequent addition of a base.

Step (c)

The reaction of the compound obtained in step (b) with the basegenerally takes place in the presence of an inert solvent.

Preferably, the compound obtained in step (b) is reacted with an aqueousbase, particularly sodium hydroxide, conveniently in a diluent such aswater, methanol, ethanol, tetrahydrofuran, dioxane, toluene,dichloromethane, chloroform, acetone, methylethylketone orchlorobenzene, or mixtures of these diluents, particularly in a mixtureof dichloromethane, tetrahydrofuran and water, optionally in thepresence of an organic base, e.g. triethylamine,N-ethyldiisopropylamine, pyridine or 4-dimethylaminopyridine and theother reaction products obtained in steps (a) and (b), e.g. phosphorusoxychloride, at temperatures from 0 to 120° C., preferably 10 to 100° C.The reaction is generally carried out at normal pressure using 1.0 to10, preferably 6 to 9 mol of a base, based on 1 mol of the chlorinatingreagent. The reaction is generally complete, under the conditionsspecified, after a few minutes to several hours, 0.1 to 24 hours,preferably 0.1-2 h. The crude product obtained is generally isolated byextraction and/or crystallisation and optionally purified byrecrystallisation.

In a particularly preferred embodiment of the process according to theinvention water is added to the reaction mixture obtained in step (b),with cooling, and the pH is adjusted with sodium hydroxide solution toan alkaline level of 7.5-13, particularly 9-11. The phases are separatedand the aqueous phase is extracted with dichloromethane. The combinedorganic phases are preferably decolorised with activated charcoal,filtered and evaporated to dryness in vacuo. The residue is taken up inboiling methylethylketone, decolorised again, filtered and thenevaporated down. The mixture is cooled to 0 to 10° C. and stirred for afurther 2 hours at this temperature. The product that crystallises outis filtered off, washed with methylethylketone and ethyl acetate anddried.

In a preferred embodiment of the process according to the invention forpreparing the compound of formula II:

-   -   the compound of formula V is heated in step (d) with an acid in        a high-boiling solvent;    -   the compound obtained in step (d) is reacted with bromine in the        presence of a tertiary amine.        Stage V→II        Step (d)

The cyclising of the compound of formula V generally takes place in thepresence of an inert diluent.

Preferably, the compound of formula V is reacted with an acid selectedfrom among hydrochloric acid, sulphuric acid, p-toluenesulphonic acid,phosphoric acid, a carboxylic acid such as acetic acid, propionic acid,pivalic acid, trifluoroacetic acid and silica gel, optionally in thepresence of a base such as pyridine, conveniently in a high-boilingdiluent such as n-butanol, amylalcohol, toluene, xylene, chlorobenzene,or mixtures of these diluents at temperatures from 20 to 160° C.,preferably 60 to 140° C. The reaction is generally carried out at normalpressure using 1.5 to 6.0, preferably 1.9 to 4.0, particularly 3.2 to3.8 mol of an acid, based on 1 mol of the compound of formula V. Thereaction is generally complete, under the conditions specified, after 15to 600 minutes, preferably 30 to 180 minutes. The crude product obtainedis generally further processed in the next step without any otherpurification.

In a particularly preferred embodiment of the process according to theinvention, one part of2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]acetamide is added to amixture of 4 to 12 parts of n-butanol and 0.4 to 1.2 parts of glacialacetic acid at 80-110° C. and refluxed for 0.5 to 2 hours.

Step (e)

The reaction of the compound obtained in step (d) with a brominatingagent generally takes place in the presence of an inert solvent.

Preferably, the compound obtained in step (d) is reacted with abrominating agent selected from among bromine, N-bromosuccinimide and1,3-dibromo-5,5-dimethylhydantoin, conveniently in a diluent such asn-butanol, amylalcohol, toluene, xylene, chlorobenzene, or mixtures ofthese diluents, optionally in the presence of an organic base, e.g.triethylamine, N-ethyldiisopropylamine or pyridine, at temperatures from−20 to +60° C., preferably −10 to +20° C. The reaction is generallycarried out at normal pressure, using 0.9 to 2.0, preferably 1.1 to 1.9,particularly 1.2 to 1.8 mol of a brominating agent based on 1 mol of thecompound of formula V. The reaction is generally complete, under theconditions specified, after 15 to 600 minutes, preferably 30 to 240minutes. The crude product obtained is generally isolated bycrystallisation and optionally purified by recrystallisation.

In a particularly preferred embodiment of the process according to theinvention the reaction mixture obtained in step (d) is cooled to ambienttemperature, and pyridine and about 1.2 to 1.8 mol bromine based on 1mol of the compound of formula V used are added. The resulting mixtureis then stirred for a further 0.1 to 4 hours, cooled to 0-20° C. andstirred for another 1 to 3 hours at this temperature. The product thatcrystallises out is isolated by filtration, washed with aqueous ethanoland dried.

The compound of formula V needed as a starting material is known, forexample, from published German application DE 22 17 157 or U.S. Pat. No.4,094,984 and can be prepared in a manner known per se by reacting a2-amino-3-arylthiophene with bromoacetylbromide and ammonia.

Other advantageous aspects of the method according to the invention arethe high space/time yields of the present process and the high yield andpurity of the associated intermediate products, which can be furtherprocessed without being purified by chromatography.

The Examples that follow serve to illustrate the processes carried outby way of example for preparing the compound of formula I. They are tobe understood as being possible methods given solely as examples withoutrestricting the invention to their content.

EXAMPLE 17-Bromo-5-(2-chlorophenyl)-1,3-dihydrothieno[2,3-e]-1,4-diazepine-2-one,(1)

220 g (0.746 mol) of2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]acetamide (prepared byreacting 2-amino-3-(2-chlorobenzoyl)thiophene with bromoacetylbromideand subsequently piping in gaseous ammonia) are added at 110° C. to amixture of 1.8 l of n-butanol and 150 ml of glacial acetic acid. Themixture is refluxed for 1 hour, cooled to ambient temperature and 330 mlof pyridine and 57 ml (178.8 g, 1.12 mol) of bromine are added withcooling. Then the mixture is stirred for another 0.5 to 2 hours, cooledto 5 to 10° C. and stirred for a further 2 hours at this temperature.The product that crystallises out is isolated by filtration, washed with50% ethanol and dried overnight in vacuo at 60° C. Yield: 152 g (57.3%).

EXAMPLE 2

Brotizolam

A suspension of 50 g (0.14 mol) of (1) in 2.5 ml of pyridine and 200 mlof dichloromethane is added dropwise to a suspension of 36 g (0.183 mol)of phosphorus pentachloride in 250 ml of dichloromethane at 5-10° C.with cooling. The mixture is stirred for 1 hour at 10° C. and a solutionof 17 g (0.28 mol) of acetic acid hydrazide in 170 ml oftetrahydrofuran, heated to 40-50° C., is added dropwise with cooling at10-20° C. The mixture is then stirred for 1 hour at ambient temperatureand then refluxed for 5 to 18 hours. It is then cooled to ambienttemperature, 380 ml water are added with cooling and the mixture isadjusted to an alkaline pH with 45% sodium hydroxide solution.

The phases are separated and the aqueous phase is extracted with 100 mlof dichloromethane. 5 g of activated charcoal are added to the combinedorganic phases which are then stirred for 10 minutes, filtered andevaporated to dryness in vacuo. The residue is taken up in 750 ml ofboiling methylethylketone, 5 g of activated charcoal are added and theresulting mixture is refluxed for another 10 min. The suspension isfiltered, then 570 ml of solvent are distilled off. The mixture isallowed to cool slowly to ambient temperature and then cooled to 5° C.and stirred for 2 hours at this temperature. The product thatcrystallises out is filtered off, washed with 30 ml of coldmethylethylketone and 50 ml of cold ethyl acetate and dried overnight at60° C. in vacuo. Yield: 36.6 g (66%) of brotizolam.

1. A process for preparing a6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepine of the formulaI,

wherein R¹ denotes a hydrogen or halogen atom or a C₁-C₆ alkyl group, R²denotes a hydrogen or halogen atom or a C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl,C₃-C₆ cycloalkyl group or a 5- or 6-membered oxygen-, sulphur- ornitrogen-containing heterocyclic group which may optionally besubstituted at the nitrogen atom by a C₁-C₃ alkyl group, and R³ denotesa hydrogen or halogen atom, in which process, a5-aryl-2-chlorothieno[2,3-e]-1,4-diazepine of the formula III

wherein R¹ and R³ are as herein defined, is reacted with anacylhydrazine of the formula IVR2—CO—NH—NH2  (IV) wherein R² is as hereinbefore defined.
 2. The processaccording to claim 12, wherein R¹ denotes a bromine atom, R² denotes amethyl group, and R³ denotes a chlorine atom.
 3. The process accordingto claim 12, wherein the compound of the formula (III) is reacted withacetic acid hydrazide at a temperature below 100° C. in the presence ofan inert diluent.